Comparable outcomes for GvHD prophylaxis with PTCy or ATG in patients with AML transplanted from matched sibling donors

T-cell depletion with antithymocyte globulin (ATG) has become an important part of graft-versus-host disease (GvHD) prophylaxis in the setting of matched related donor transplantation. Recently, the use of posttransplant cyclophosphamide (PTCy) in patients receiving allogeneic hematopoietic stem cell transplants (allo-HSCT) from haploidentical donors has been shown to be effective at reducing the risk of acute GvHD (aGvHD) and chronic GvHD (cGvHD) in this setting. It has been suggested that PTCy may also be feasible in alternative transplant settings.

 

The Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) sought to compare the GvHD prophylaxis regimens, ATG vs PTCy, in adult patients with acute myeloid leukemia (AML) receiving allo-HSCT from HLA-identical siblings. The data from the retrospective analysis were recently published in Cancer, and the GvHD Hub is pleased to provide a summary.

Study design

A retrospective study by the ALWP of the EBMT involving over 600 transplant centers, to compare ATG with PTCy as GvHD prophylaxis in adult patients (age ≥ 18 years) undergoing HLA-identical sibling allo-HSCT for the treatment of AML. Patients were in their first complete remission at the time of allo-HSCT and received their first allo-HSCT between 2008 and 2018. The primary endpoint was the cumulative incidence of GvHD.

Patient characteristics

A total of 2,110 patients fulfilled the inclusion criteria and were included in the analysis (ATG, n = 1,913; PTCy, n = 197). Patient characteristics are presented in Table 1.

Table 1. Patient characteristics¹

Characteristic	ATG (n = 1,913)	PTCy (n = 197)	p value
allo-HSCT, allogeneic hematopoietic stem cell transplantation; ATG, antithymocyte globulin; PTCy, posttransplant cyclophosphamide. *The cytogenetic risk was defined according to the refined UK Medical Research Council criteria. Significant differences between groups are shown in bold.
Median age at allo-HCT, years (range)	54 (18–72)	47 (18–74)	< 0.01
Male sex, %	53	55	0.55
Female donor into male recipient, %	24	26	0.55
Cytogenetic risk, %*			0.51
Good	3	4
Intermediate	45	44
Poor	19	15
NA/failed	33	37
Karnofsky performance status < 90%	24	21	0.39
Patient cytomegalovirus serology, %			< 0.01
Positive	70	80
Negative	30	20
Interval from diagnosis to allo-HSCT, months (range)	4.8 (1–18)	4.3 (1–17)	< 0.01
Median year of allo-HSCT (range)	2014 (2008–2018)	2015 (2009–2018)	< 0.01
Conditioning regimen			< 0.01
Myeloablative	48	59
Reduced intensity	52	41
Source of stem cells			< 0.01
Bone marrow	5	30
Peripheral blood stem cells	95	70
Median follow-up, months (range)	28 (12–54)	19 (5–34)	< 0.01

Results

GvHD

• Neutrophil engraftment was 99.5% across both groups, however, the time to engraftment was significantly longer in the PTCy treatment group (Table 2).
• Levels of aGvHD were comparable between groups, but the incidence of cGvHD was lower in patients treated with ATG vs PTCy (Table 2).
• Multivariate analysis confirmed that the risk of cGvHD was lower in patients who received ATG vs PTCY:
  • All-grade GvHD: HR, 0.71; 95% CI, 0.52–0.97 (p < 0.04)
  • Extensive cGvHD: HR, 0.60; 95% CI, 0.38–0.93 (p < 0.03)
• However, these lower rates of cGvHD were only seen in patients who received one additional immunosuppressive drug in association with ATG. Patients receiving ≥ 2 associated drugs demonstrated no difference between ATG and PTCy.
• Positive cytomegalovirus serology and female donor to male recipient were independently associated with a higher risk of Grade 2–4 aGvHD and a higher risk of cGvHD, respectively.
• Results for aGvHD and cGvHD rates were confirmed in a pair-matched analysis.

• Of the patients in the ATG and PTCy groups, 33% and 29% died, respectively.
  • The primary cause of death was disease recurrence: 56% in the ATG group and 58% in the PTCy group.
  • Deaths related to infection or GvHD were reported in 4% and 6%, respectively, across both groups.
• The 2-year relapse incidence and non-relapse mortality rates were comparable between the two groups.

Patient outcomes

• At 2 years, leukemia-free survival (LFS), overall survival (OS), and GvHD/relapse-free survival (GRFS) were not significantly different between patients who received ATG vs PTCY (Table 2).
• Factors associated with lower LFS, OS, and GRFS:
  • Incremental age of 10 years
  • Secondary AML diagnosis
  • Poor karyotype
• The use of peripheral blood stem cells was associated longer LFS, OS, and GRFS.
• A Karnofsky performance status of ≥ 90% was associated with longer LFS.

Table 2. Outcomes in patients receiving ATG vs PTCy prophylaxis with HLA-identical sibling allo-HSCT for the treatment of AML¹

Outcomes, %	ATG (n = 1,913)	PTCy (n = 197)	p value
aGvHD, acute graft-versus-host disease; AML, acute myeloid leukemia; ATG, antithymocyte globulin; cGvHD, chronic GvHD; GRFS, GvHD/relapse-free survival; LFS, leukemia-free survival; OS, overall survival; PTCy, posttransplant cyclophosphamide. Significant differences between groups are shown in bold.
aGvHD
Grade 2–4	17	19	0.81
Grade 3/4	6	6	0.91
cGvHD
All grades	30	37	0.02
Extensive	12	16	< 0.01
Median time to engraftment, days	17	20	< 0.01
LFS at 2 years	58	55	0.75
GRFS at 2 years	49	44	0.20
OS at 2 years	65	64	0.61

Conclusion

In the allo-HSCT setting, GvHD can be hugely debilitating and represents one of the main influencers of impaired quality of life and survival. Overall, encouraging rates of both aGvHD and cGvHD were observed in this study compared with those obtained using conventional immunosuppressive agents such as cyclosporine A plus either methotrexate or mycophenolate mofetil. The results from this study support the use of PTCy as an alternative option to ATG in the HLA-identical setting. The use of ATG yielded lower cumulative incidences of cGvHD, however, only when it was used in association with one additional immunosuppressive drug. This confirms previous results showing improved GvHD rates when using combinations of drugs as GvHD prophylaxis.

 

The authors noted the retrospective nature of this analysis and the low number of patients treated with PTCy as limitations of the study, suggesting that important influencing factors may have been disregarded. Furthermore, there was a lack of information regarding the rationale behind GvHD prophylaxis choices made by the treating physician.